Process for preparing 2-(aminomethylidene)-4,4-difluoro-3-oxobutyric esters

ABSTRACT

The present invention relates to a process for preparing difluoromethyl-substituted pyrazol-4-ylcarboxylic acids and their esters, 2-(aminomethylidene)-4,4-difluoro-3-oxobutteric esters of the formula (I) 
                         
in which R 1 , R 2  and R 3  independently of one another are C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 3 -C 10 -cycloalkyl or benzyl or NR 2 R 3  is a 5- to 10-membered heterocyclic radical, to a process for preparing compounds of the formula (I) wherein an appropriate 3-aminoacrylic ester is reacted with difluoroacetyl fluoride and to the use of compounds of the formula (I) in the process for preparing difluoromethyl-substituted pyrazol-4-ylcarboxylic acids and their esters.

This application is a National Stage application of InternationalApplication No.

PCT/EP2009/055283 filed Apr. 30, 2009, the entire contents of which ishereby incorporated herein by reference. This application also claimspriority under 35 U.S.C. §119 to European Patent Application No.08155612.8, filed May 2, 2008, the entire contents of which is herebyincorporated herein by reference.

The present invention relates to a process for preparing2-(aminomethylidene)-4,4-difluoro-3-oxobutyric esters, and to their usein the process for preparing the difluoromethyl-substitutedpyrazol-4-ylcarboxylic acids and esters thereof. The present inventionalso relates to novel 2-(aminomethylidene)-4,4-difluoro-3-oxobutyricesters.

WO 92/12970 describes(3-difluoromethyl-1-methylpyrazol-4-yl)carboxamides and their use asfungicides. The preparation starts with a 4,4-difluoro-3-oxobutyricester which is reacted successively with triethyl orthoformiate and withmethylhydrazine, which gives a3-difluoromethyl-1-methylpyrazol-4-carboxylic ester. This is thenhydrolyzed to give the corresponding carboxylic acid. This is convertedinto the corresponding acid chloride and then, using a suitable amine,into the corresponding amide. However, providing the4,4-difluoro-3-oxobutyric ester required as starting material isrelatively expensive and difficult.

WO 2005/044804 describes alkyl esters of fluoromethyl-substitutedheterocyclic carboxylic acids and their preparation by halogen exchangeon corresponding chloromethyl-substituted heterocyclic carboxylic estersusing fluorinating agents. However, the use of fluorinating agents isexpensive, and special demands with regard to safety measures which haveto be taken and to the apparatus used have to be met.

WO 2005/042468 describes the preparation of2-(dialkylaminomethylidene)-4,4-dihalo-3-oxobutyric esters by reactingdialkylaminoacrylic esters with dihaloacetyl halides in the presence ofa base. Here, in order to prevent the formation of dihaloketenes, thebases used are in particular aqueous solutions of alkali metal andalkaline earth metal hydroxides. However, this reaction does not givesatisfactory yields. The2-(dialkyl-aminomethylidene)-4,4-dihalo-3-oxobutyric esters obtained areconverted with C₁-C₄-alkylhydrazines into the corresponding N-alkylateddihalomethyl-substituted pyrazol-4-ylcarboxylic esters. However, thisreaction provides no satisfactory selectivity for the 3-dihalomethylcompound over the corresponding 5-dihalomethyl compound. The subsequentseparation of the two isomers formed is relatively complicated.

Accordingly, it is an object of the present invention to provide afurther process for preparing (3-difluoromethylpyrazol-4-yl)carboxylicesters and derivatives thereof whose starting materials can be providedwith low expense and in higher yields. Furthermore, from these startingmaterials, it should be possible to prepare the(3-difluoromethylpyrazol-4-yl)carboxylic esters in high yield, with aselectivity which is as high as possible, over the reaction to the(5-difluoromethylpyrazol-4-yl)carboxylic ester, which usually takesplace as a side reaction.

Surprisingly, it has been found that this object is achieved by aprocess for preparing compounds of the formula (I)

in which

-   R¹ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₃-C₁₀-cycloalkyl    or benzyl, where the two last mentioned radicals are unsubstituted    or have 1, 2 or 3 substituents independently of one another selected    from the group consisting of halogen, CN, nitro, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;-   R² and R³ independently of one another are C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₃-C₁₀-cycloalkyl or benzyl, where    the two last mentioned radicals are unsubstituted or have 1, 2 or 3    substituents independently of one another selected from the group    consisting of halogen, CN, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl,    C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; or-   R² together with R³ and the nitrogen atom to which the two radicals    are attached are an optionally substituted 5- to 10-membered    heterocyclic radical which, in addition to the nitrogen atom, may    contain a further 1, 2 or 3 heteroatoms selected from the group    consisting of O, N and S as ring members;    wherein    a compound of the formula (II)

in which R¹, R² and R³ have one of the meanings given above;is reacted with difluoroacetyl fluoride.

By this process according to the invention, it is possible to provide,with low expenses and in high yields, particularly suitable startingmaterials for a process for preparing(3-difluoromethylpyrazol-4-yl)carboxylic esters.

Accordingly, the present invention furthermore provides compounds of theformula (I)

in which R¹ has the meaning given above and

-   R² together with R³ and the nitrogen atom to which the two radicals    are attached are an optionally substituted 5- to 10-membered    heterocyclic radical which, in addition to the nitrogen atom, may    contain a further 1, 2 or 3 heteroatoms selected from the group    consisting of O, N and S as ring members.

These compounds of the formula (I) can be provided in a good yield, andthey are particularly suitable for conversion with N-substitutedhydrazine compounds into (3-difluoromethylpyrazol-4-yl)carboxylicesters, especially with respect to yield and selectivity for the desiredisomer over the (5-difluoromethyl-pyrazol-4-yl)carboxylic esterbyproduct.

The E configuration shown here and in the formulae below of the C═Cdouble bond in the compounds I and II is only one possible embodiment ofthe compounds I and II. The invention relates both to the E isomer shownand to the Z isomer and in particular to mixtures of the isomers.

The terms for organic groups used in the definition of the variables,such as, for example, the term “halogen”, are collective terms whichrepresent the individual members of these groups of organic moieties.

In each case, the prefix C_(x)-C_(y) denotes the number of possiblecarbon atoms.

In each case, the term “halogen” denotes fluorine, bromine, chlorine oriodine, especially fluorine, chlorine or bromine.

The term “C₁-C₆-alkyl”, as used herein and in the alkyl moieties ofC₁-C₆-alkoxy, denotes a saturated straight-chain or branched hydrocarbongroup comprising 1 to 6 carbon atoms, especially 1 to 4 carbon atoms,for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyland isomers thereof. C₁-C₄-alkyl comprises, for example, methyl, ethyl,propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and1,1-dimethylethyl.

The term “C₁-C₆-alkoxy” describes straight-chain or branched saturatedalkyl groups comprising 1 to 6 carbon atoms, which groups are attachedvia an oxygen atom. Examples of C₁-C₆-alkoxy include methoxy, ethoxy,n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy,1,1-dimethylethoxy, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy,3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy,2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyand 1-ethyl-2-methylpropoxy. Examples of C₁-C₄-alkoxy include methoxy,ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy,2-methylpropoxy and 1,1-dimethylethoxy.

The term “C₁-C₆-haloalkyl”, as used herein and in the haloalkyl moietiesof C₁-C₆-haloalkoxy, describes straight-chain or branched alkyl groupshaving 1 to 6 carbon atoms, where some or all of the hydrogen atoms ofthese groups are replaced by halogen atoms. Examples of these areC₁-C₄-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl,trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2,2,2-trichloroethyl and pentafluoroethyl.

The term “C₁-C₆-haloalkoxy” describes straight-chain or branchedsaturated haloalkyl groups comprising 1 to 6 carbon atoms, which groupsare attached via an oxygen atom. Examples of these are C₁-C₄-haloalkoxy,such as chloromethoxy, bromomethoxy, dichlorornethoxy, trichloromethoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy,dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy,1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,2,2,2-trichloroethoxy and pentafluoroethoxy.

The term “C₂-C₆-alkenyl” describes straight-chain and branchedunsaturated hydrocarbon groups comprising 2 to 6 carbon atoms and atleast one carbon-carbon double bond, such as, for example, ethenyl,1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

The term “C₃-C₁₀-cycloalkyl”, as used herein, describes mono-, bi- ortricyclic hydrocarbon groups comprising 3 to 10 carbon atoms, especially3 to 6 carbon atoms. Examples of monocyclic groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Examplesof bicyclic groups include bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl. Examples of tricyclicgroups are adamantyl and homoadamantyl.

In connection with the definition of the group —NR²R³, the term “5- to10-membered heterocyclic radical” denotes a nitrogenous mono- orbicyclic group having 5, 6, 7, 8, 9 or 10 ring members, which isattached via the nitrogen atom to the remainder of the compound of theformula (I) or (II), which, in addition to the nitrogen atom, may have afurther 1, 2 or 3 heteroatoms selected from the group consisting of O, Nand S as ring members and which is unsubstituted or may have 1, 2 or 3substituents. The substituents, provided they are attached to a carbonatom of the heterocyclic radical, are preferably selected from the groupconsisting of halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxyand C₁-C₄-haloalkoxy and, provided they are attached to a furthernitrogen atom of the heterocyclic radical, are preferably selected fromthe group consisting of C₁-C₄-alkyl and C₁-C₄-haloalkyl. Examples of 5-to 10-membered heterocyclic radicals are pyrrol-1-yl, pyrrolidin-1-yl,oxazolidin-3-yl, thiazolidin-3-yl, imidazol-1-yl, imidazolin-1-yl,3-methylimidazolin-1-yl, 3-ethylimidazolin-1-yl,3-propylimidazolin-1-yl, 3-(1-methylethyl)imidazolin-1-yl,3-butylimidazolin-1-yl, 3-(1,1-dimethylethyl)imidazolin-1-yl,pyrazol-1-yl, pyrazolidin-1-yl, 2-methylpyrazolidin-1-yl,2-ethylpyrazolidin-1-yl, 2-propylpyrazolidin-1-yl,2-(1-methylethyl)pyrazolidin-1-yl, 2-butylpyrazolidin-1-yl,2-(1,1-dimethylethyl)pyrazolidin-1-yl, piperidin-1-yl, morpholin-4-yl,thiamorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-propylpiperazin-1-yl,4-(1-methylethyl)piperazin-1-yl, 4-butylpiperazin-1-yl,4-(1,1-dimethylethyl)piperazin-1-yl, indol-1-yl, indolin-1-yl,isoindol-1-yl, isoindolin-1-yl, indazol-1-yl, indazolin-1-yl,2-methylindazolin-1-yl, indazolin-2-yl and 1-methylindazolin-1-yl, wherethe heterocyclic groups mentioned above are unsubstituted, or 1, 2 or 3of the ring carbon atoms carry a substituent selected from the groupconsisting of halogen, CN, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

The carbon-carbon double bond in the compounds of the formulae (I) and(II) can have the E or the Z configuration (or the cis or transconfiguration, based on the relative arrangement of the group NR²R³ andthe group —C(O)OR¹).

The reactions described herein are carried out in reaction vesselscustomary for such reactions, where the reaction may be carried outeither continuously or batchwise. In general, the reactions in questionwill be carried out at atmospheric pressure. However, the reactions canalso be carried out under superatmospheric pressure.

In the compounds of the formulae (I) and (II), R¹ is preferablyC₁-C₆-alkyl, C₃-C₁₀-cycloalkyl or benzyl, where the two last mentionedradicals are unsubstituted or have 1, 2 or 3 substituents. Preferably,R¹ in the compounds of the formulae (I) and (II) is C₁-C₄-alkyl,C₃-C₆-cycloalkyl or benzyl. Very particularly preferably, R¹ in thecompounds of the formulae (I) and (II) is C₁-C₄-alkyl.

In the compounds of the formulae (I) and (II), R² and R³ independentlyof one another are preferably C₁-C₄-alkyl, or R² together with R³ andthe nitrogen atom to which the two radicals are attached are anoptionally substituted 5- to 10-membered heterocyclic radical which, inaddition to the nitrogen atom, may comprise a further 1, 2 or 3heteroatoms selected from the group consisting of O, N and S as ringmembers.

Particularly preferably, R² and R³ together with the nitrogen atom towhich the two radicals are attached are an optionally substituted 5- to10-membered heterocyclic radical which, in addition to the nitrogenatom, may contain a further 1, 2 or 3 heteroatoms selected from thegroup consisting of O, N and S as ring members, i.e. the group NR²R³ isa 5- to 10-membered heterocyclic radical which is attached via nitrogen.These preferences apply both to the compounds of the formulae (I) and(II) per se and to their use in the process according to the inventionfor preparing (3-difluoromethylpyrazol-4-yl)carboxylic esters.

In the compounds of the formulae (I) and (II), the group NR²R³ veryparticularly preferably is a saturated, optionally substituted 5- or6-membered heterocyclic radical which, in addition to the nitrogen atom,may contain a further heteroatom selected from the group consisting ofO, N and S as ring member. In particular, the group NR²R³ ispyrrolidin-1-yl, oxazolidin-3-yl, 3-methylimidazolin-1-yl,piperidin-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl. Specifically,the group NR²R³ in the compounds of the formulae (I) and (II) ispiperidin-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl.

In the process according to the invention for preparing compounds of theformula (I), the compound of the formula (II) is usually employed in anamount of from. 0.2 to 3 mol, preferably from 0.3 to 1.5 mol, especiallyfrom 0.5 to 1.0 mol and particularly preferably from 0.9 to 1.0 mol, ineach case based on 1 mol of difluoroacetyl fluoride.

The reaction is carried out by bringing the starting materials, i.e. thecompound of the formula (II) and the difluoroacetyl fluoride, intocontact with one another, preferably in a suitable solvent in a reactionvessel, where the compound of the formula (II) and, if appropriate, thesolvent are generally initially charged in the reaction vessel.

The reaction of the compound of the formula (II) with difluoroacetylfluoride is usually carried out at a temperature in the range of from−70 to +50° C., preferably from −30 to +20° C. and particularlypreferably from −10 to 0° C. In a particular embodiment, the temperatureis initially adjusted to from −50 to −10° C. and, during the course ofthe reaction, increased to from 10 to 40° C., in particular roomtemperature.

The reaction of the compound of the formula (II) with difluoroacetylfluoride is usually carried out at atmospheric pressure. However, owingto the low boiling point of difluoroacetyl fluoride, it may, dependingon the chosen reaction temperature, be advantageous to carry out thereaction under elevated pressure. Suitable reaction pressures are, forexample, in a range of from 0.5 to 10 bar. Suitable pressure-resistantreactors are also known to the person skilled in the art and aredescribed, for example, in Ullmanns Enzyklopädie der technischen Chemie[Ullmanns Encyclopedia of Industrial Chemistry], vol. 1, 3rd edition,1951, p. 769 ff.

In the process according to the invention for preparing compounds of theformula (I), the reaction of the compound of the formula (II) withdifluoroacetyl fluoride is preferably carried out essentiallyanhydrously, i.e. in a dry organic solvent.

Here and below, dry solvent means that the solvent has a water contentof less than 500 ppm and in particular of less than 100 ppm.

Examples of suitable organic solvents are nonpolar aprotic solvents, forexample aromatic hydrocarbons, such as benzene, toluene, xylenes, or(cyclo)aliphatic hydrocarbons, such as hexane, cyclohexane and the like,and also mixtures of the solvents mentioned above.

Examples of suitable organic solvents are likewise aprotic polarsolvents, for example cyclic and acyclic ethers, such as diethyl ether,tert-butyl methyl ether (MTBE), diisopropyl ether, cyclopentyl methylether, tetrahydrofuran (THF) or dioxane, cyclic or acyclic amides, suchas dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, ureas,such as N,N′-dimethyl-N,N′-ethyleneurea (DMEU),N,N′-dimethyl-N,N′-propyleneurea (DMPU) or tetramethylurea, or aliphaticnitriles, such as acetonitrile or propionitrile, and also mixtures ofthe solvents mentioned above.

Also suitable are mixtures of the nonpolar aprotic organic solventsmentioned above with polar aprotic solvents.

In a specific embodiment of the process according to the invention, thecompound of the formula (II) is reacted with difluoroacetyl fluoridewithout addition of a base different from the compound of the formula(II).

In a further specific embodiment of the process according to theinvention, the compound of the formula (II) is reacted withdifluoroacetyl fluoride in the presence of a base different from thecompound of the formula (II).

Suitable bases different from the compound of the formula (II) areorganic bases, for example acyclic tertiary amines, e.g.tri-C₁-C₆-alkylamines such as trimethylamine, triethylamine,tributylamine, diisopropylethylamine, tert-butyldimethylamine,N—C₃-C₆-cycloalkyl-N,N-di-C₁-C₆-alkylamines orN,N-bis-C₃-C₆-cycloalkyl-N—C₁-C₆-alkylamines such asethyldicyclohexylamine, cyclic tertiary amines, e.g.N—C₁-C₆-alkyl-nitrogen heterocycles such as N-methylpyrrolidine,N-methylpiperidine, N-methylmorpholine, N,N′-dimethylpiperazine,pyridine compounds such as pyridine, collidine, lutidine or4-dimethylaminopyridine, and bicyclic amines, such asdiazabicycloundecene (DBU) or diazabicyclononene (DBN).

Also suitable as bases different from the compound of the formula (II)are inorganic compounds, for example alkali metal and alkaline earthmetal carbonates, such as lithium carbonate or calcium carbonate, alkalimetal bicarbonates, such as sodium bicarbonate, alkali metal andalkaline earth metal oxides, such as lithium oxide, sodium oxide,calcium oxide or magnesium oxide, alkali metal and alkaline earth metalhydrides, such as lithium hydride, sodium hydride, potassium hydride orcalcium hydride, or alkali metal amides, such as lithium amide, sodiumamide or potassium amide.

Preferably, the base different from the compound of the formula (II) inthe process according to the invention for preparing compounds of theformula (I) is selected from organic bases. Particularly preferably, thebase is selected from acyclic tertiary amines, especially triethylamine.

The base different from the compound of the formula (II) can be employedeither in approximately equimolar amounts, based on the compound (II),for example in an amount of from about 0.8 to 1.2 mol per mole of thecompound (II), or in catalytic amounts, based on the compound (II), forexample in an amount of from about 0.001 to 0.2 mol per mole of thecompound (II). However, the base can also be employed in a large excessbased on the compound of the formula (II), for example as solvent.

Usually, the compound of the formula (I) is isolated under approximatelypH-neutral conditions, i.e. at a pH in the range of from 4 to 10, orunder non-aqueous conditions, in order to prevent excess hydrolysis ofthe group —C(O)OR¹.

However, for the conversion described below into the correspondingpyrazol-4-ylcarboxylic ester, it is not necessary to isolate thecompounds of the formula (I). On the contrary, it has been found to beadvantageous to dispense with isolating the compound (I) and to convertit as a crude product or in the form of the reaction mixture obtained inthe process according to the invention into the correspondingpyrazol-4-ylcarboxylic esters.

The process according to the invention yields the compounds of theformula (I) from the compounds of the formula (II) in good to very goodyields, i.e. generally in yields of at least 70% and frequently of atleast 80%.

The compounds of the general formula (II) are commercially available orcan be prepared analogously to known compounds, as illustrated, forexample, in scheme 1 or 2.

Scheme 1 shows the preparation of compounds of the formula (II) byreacting an α,β-unsaturated ester of the formula (VI.a) in which R¹ hasone of the meanings given above and LG is a leaving group, such as, forexample, an alkoxy group, for example C₁-C₆-alkoxy, with an amine of theformula NHR²R³ in which R² and R³ have one of the meanings given above,in the presence of a base such as, for example, K₂CO₃. Suitable methodsfor carrying out this reaction are known to the person skilled in theart.

Alternatively, compounds of the formula (II) can be provided analogouslyto EP 0 388 744 by reacting a β-hydroxyacrylic ester salt of the formula(VI.b) in which R¹ has one of the meanings mentioned above and M⁺ is,for example, an alkali metal cation, such as Na⁺ or K⁺, with an ammoniumchloride of the formula NHR²R³*HCl.

Compounds of the formula (VI.b) can be provided, for example, byreacting the corresponding acetic ester with CO and an alkoxide of theformula M⁺⁻O-Alk in which Alk is, for example, C₁-C₄-alkyl.

When converting the compounds of the formula (I) intodifluoromethylpyrazolyl-carboxylic esters, the amines of the formulaNHR²R³ are obtained as a byproduct, and after the reaction has beencarried out, they can advantageously be recovered and, if appropriate,converted into their hydrochlorides NHR²R³*HCl, to be used again forproviding compounds of the formula (II) according to scheme 1 or 2.

The compounds of the formula (I), prepared by the process according tothe invention, in which R² together with R³ and the nitrogen atom towhich the two radicals are attached are a heterocyclic radical arelikewise novel. Accordingly, another subject matter of the inventionrelates to the compounds of the formula (I)

in which R¹ has one of the meanings given above and R² together with R³and the nitrogen atom to which the two radicals are attached are anoptionally substituted 5- to 10-membered heterocyclic radical which, inaddition to the nitrogen atom, may contain a further 1, 2 or 3heteroatoms selected from the group consisting of O, N and S as ringmembers.

The compounds of the formula (I) in which R² together with R³ and thenitrogen atom to which the two radicals are attached are a heterocyclicradical are suitable in a particularly advantageous manner for preparingdifluoromethyl-substituted pyrazol-4-ylcarboxylic esters. Accordingly, afurther subject matter of the invention relates to a process forpreparing difluoromethyl-substituted pyrazol-4-ylcarboxylic esters ofthe formula (III)

in which

-   R¹ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₃-C₁₀-cycloalkyl    or benzyl, where the two last mentioned radicals are unsubstituted    or have 1, 2 or 3 substituents independently of one another selected    from the group consisting of halogen, CN, nitro, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; and-   R⁴ is hydrogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₁₀-cycloalkyl,    phenyl or benzyl where the three last mentioned radicals are    unsubstituted or have 1, 2 or 3 substituents independently of one    another selected from the group consisting of halogen, CN, nitro,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;    wherein-   a) a compound of the formula (I) is provided,

-   -   in which R¹ has one of the meanings given above and R² together        with R³ and the nitrogen atom to which the two radicals are        attached are an optionally substituted 5- to 10-membered        heterocyclic radical which, in addition to the nitrogen atom,        may contain a further 1, 2 or 3 heteroatoms selected from the        group consisting of O, N and S as ring members; and

-   b) the compound of the formula (I) provided in step a) is reacted    with a hydrazine compound of the formula (IV)    R⁴HN—NH₂  (IV)    -   in which R⁴ has one of the meanings given above.

The process according to the invention for preparing compounds of theformula (III) is associated with a number of advantages. The processaccording to the invention affords the compounds of the formula (III) ina high yield. Moreover, if R⁴ has a meaning different from H, thecompound of the formula (III) is prepared with high selectivity over the(5-difluoromethylpyrazol-4-yl)carboxylic ester formed as a byproduct.Thus, a complicated separation of the isomer mixtures may be dispensedwith or at least limited. Moreover, the process according to theinvention can be carried out both anhydrously and in the presence ofwater, simultaneously achieving satisfactory yields and excesses of thecompound of the formula (III).

Preferably, the group R¹ in the compounds of the formula (III) has oneof the meanings mentioned above as preferred meanings of the groups R¹in the compounds of the formulae (I) and (II).

In a specific embodiment of the process according to the invention, thegroup R⁴ in the compounds of the formulae (III) and (IV) has a meaningdifferent from hydrogen. By the process according to the invention, thecompounds of the formula (III) in which R⁴ has a meaning different fromhydrogen can be prepared with particularly high selectivity over thecorresponding 5-difluoromethylpyrazol-4-ylcarboxylic esters.

Preferably, the group R⁴ in the compounds of the formulae (III) and (IV)is C₁-C₄-alkyl, C₃-C₆-cycloalkyl, phenyl or benzyl, where the three lastmentioned radicals are unsubstituted or have 1, 2 or 3 substituentsindependently of one another selected from the group consisting ofhalogen, C₁-C₄-alkyl and C₁-C₄-alkoxy. With particular preference, R⁴ inthe compounds of the formulae (III) and (IV) is C₁-C₆-alkyl, inparticular C₁-C₄-alkyl and especially methyl.

Preferably, the provision of a compound of the formula (I) (step a) inthe process according to the invention for preparing compounds of theformula (III) is carried out by the above-described process forpreparing compounds of the formula (I).

In a specific embodiment of the process according to the invention forpreparing compounds of the formula (III), a reaction mixture is reactedwithout prior isolation of the compound of the formula (I) with thehydrazine compound of the formula (IV), wherein the reaction mixturecontains a compound of the formula (I) and has been prepared by theprocess described above.

Step b)

Preferably, the hydrazine compound of the formula (IV) is employed inequimolar amounts or in excess, based on the component of the formula(I), a relatively large excess of the compound (IV), for example of morethan 20 mol %, generally not being required. Preferably, from 1.0 to 1.2mol, in particular from about 1.01 to 1.15 mol, of the hydrazinecompound (IV) are employed per mole of the compound (I).

The hydrazine compound of the formula (IV) is preferably aC₁-C₆-alkylhydrazine and in particular a C₁-C₄-alkylhydrazine;specifically, the compound of the general formula (IV) ismethylhydrazine.

If R⁴ in the compounds of the formula (III) is hydrogen, the compound ofthe formula (IV) used is preferably hydrazine hydrate.

The reaction of the compound of the formula (I) with the hydrazinecompound (IV) is usually carried out such that the hydrazine compound ofthe formula (IV) is initially charged in a suitable solvent, the desiredreaction temperature is set and the compound of the formula (I), ifappropriate in the form of a solution and/or a reaction mixture obtainedduring the provision, is then added.

Preferably, the hydrazine compound of the formula (IV) is initiallycharged as a solution in an organic solvent or a solvent/water mixture.Alternatively, it may also be possible to add the hydrazine compound ofthe formula (IV), preferably as solution in an organic solvent or in asolvent/water mixture, to the compound of the formula (I), ifappropriate in the form of a solution in an organic solvent or in asolvent/water mixture.

Organic solvents suitable for reacting the compound of the formula (I)with the hydrazine compound (IV) are, for example, protic polarsolvents, such as aliphatic alcohols having preferably 1 to 4 carbonatoms, especially methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol or tert-butanol, nonpolar aprotic solvents, e.g. aromatichydrocarbons, such as benzene, toluene, xylenes, mesitylene, cumene,chlorobenzene, nitrobenzene or tert-butylbenzene, aprotic polarsolvents, such as cyclic or acyclic ethers, especially diethyl ether,tert-butyl methyl ether (MTBE), cyclopentyl methyl ether,tetrahydrofuran (THF) or dioxane, cyclic or acyclic amides, especiallydimethylformamide, dimethylacetamide, N-methylpyrrolidone, ureas, suchas N,N′-dimethyl-N,N′-ethyleneurea (DMEU),N,N′-dimethyl-N,N′-propyleneurea (DMPU) or tetramethylurea, or aliphaticnitriles, especially acetonitrile or propionitrile, or mixtures of thesolvents mentioned above.

The reaction of the compound of the formula (I) with the hydrazinecompound (IV) can, if appropriate, be carried out in the presence of abase.

Bases suitable for this purpose are organic bases, for example theabovementioned acyclic tertiary amines, such as trimethylamine,triethylamine, diisopropylethylamine, tert-butyldimethylamine orethyldicyclohexylamine, the abovementioned cyclic tertiary amines, suchas N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine,N,N′-dimethylpiperazine, pyridine, collidine, lutidine or4-dimethylaminopyridine, or bicyclic amines, such asdiazabicycloundecene (DBU) or diazabicyclononene (DBN).

Also suitable as bases are inorganic compounds, for example alkali metaland alkaline earth metal hydroxides, such as sodium hydroxide, potassiumhydroxide or calcium hydroxide, alkali metal and alkaline earth metaloxides, such as lithium oxide, sodium oxide, calcium oxide or magnesiumoxide, alkali metal and alkaline earth metal carbonates, such as lithiumcarbonate or calcium carbonate, alkali metal bicarbonates, such assodium bicarbonate, alkali metal and alkaline earth metal hydrides, suchas lithium hydride, sodium hydride, potassium hydride or calciumhydride, or alkali metal amides, such as lithium amide, sodium amide orpotassium amide.

The base can be employed either in approximately equimolar amounts,based on the compound (I), for example in an amount of from about 0.8 to1.2 mol per mole of the compound (I), or in catalytic amounts, based onthe compound (I), for example in an amount of from about 0.001 to 0.2mol per mole of the compound (I). However, the base may also be employedin a large excess based on the compound of the formula (II), for exampleas solvent.

By adding a base, it may in some cases be possible to achieve arelatively large excess of the 3-difluoromethylpyrazol-4-ylcarboxylicesters of the formula (III), based on the5-difluoromethylpyrazol-4-ylcarboxylic ester formed as byproduct.

In a specific embodiment of the process according to the invention forpreparing compounds of the formula (III), the reaction of the compoundof the formula (I) with the hydrazine compound of the formula (IV) iscarried out in the presence of water. Here, even a small amount of waterin the reaction mixture of 1000 ppm is sufficient. The water releasedduring the reaction is not taken into account when the water content isstated.

In general, the water content of the reaction mixture will not exceed50% by volume, frequently 30% by volume, in particular 15% by volume,and it is frequently in the range of from 0.1 to 50% by volume,preferably in the range of from 0.5 to 30% by volume, in particular inthe range of from 1 to 15% by volume.

The reaction of the compound of the formula (I) is usually carried outin the presence of water at temperatures of from −80 to +100° C. In aspecific embodiment, at the start of the reaction, the temperature isset to from −50 to +20° C., in particular from −15 to +10° C., andduring the course of the reaction it is increased to a temperature offrom +10 to +40° C., in particular to room temperature.

If the reaction of the compound of the formula (I) is carried out in thepresence of water and a base, the base is preferably selected from theinorganic compounds mentioned above, specifically from the alkali metalor alkaline earth metal bases mentioned above and in particular fromalkali metal hydroxides or alkaline earth metal hydroxides, such as NaOHor KOH. With respect to the amounts used, what was said above applies.

The process according to the invention affords the compounds of theformula (III), when reacting a compound of the formula (I) in thepresence of water, in good yields, i.e. generally in yields of at least60% and frequently of at least 70%. Furthermore, if R⁴ has a meaningdifferent from H, this embodiment of the process yields the compounds ofthe formula (III) with high selectivity over the corresponding5-difluoromethylpyrazol-4-ylcarboxylic esters, i.e. generally in a ratioof 3-difluoromethylpyrazol-4-ylcarboxylic ester to5-difluoromethylpyrazol-4-ylcarboxylic ester of at least 2.5:1 andfrequently of at least 5:1. In the presence of a suitable base, ratiosof at least 10:1 or even 20:1 are frequently obtained.

In a further specific embodiment of the process according to theinvention for preparing compounds of the formula (III), the reaction ofthe compound of the formula (I) with the hydrazine compound of theformula (IV) is carried out essentially anhydrously, i.e. the reactionmixture has a water content of less than 500 ppm and in particular ofless than 100 ppm. The water released during the reaction is not takeninto account in the stated water content.

Usually, the process according to the invention in which the reaction ofa compound of the formula (I) is carried out essentially anhydrously iscarried out at temperatures of from −80 to +100° C. In a specificembodiment, at the beginning of the reaction the temperature is set tofrom −80 to −10° C., in particular from −60 to −30° C., and increasedduring the course of the reaction to a temperature of from +10 to +40°C., in particular room temperature.

If the process according to the invention in which the reaction of acompound of the formula (I) is carried out essentially anhydrously iscarried out in the presence of a base, this base is preferably selectedfrom among alkaline earth metal and alkali metal carbonates and theorganic bases mentioned above, in particular from among the organicbases and specifically from among the pyridines and acyclic tertiaryamines mentioned above, such as pyridine or triethylamine. With respectto the amount employed, what was said above applies.

The process according to the invention in which the reaction of acompound of the formula (I) is carried out essentially anhydrouslyaffords the compounds of the formula (III) in good to very good yields,i.e. generally in yields of at least 80% and frequently of at least 90%.Furthermore, if R⁴ has a meaning different from H, this embodiment ofthe process yields the compounds of the formula (III) with very highselectivity over the corresponding5-difluoromethylpyrazol-4-ylcarboxylic esters, i.e. generally in a ratioof 3-difluoromethylpyrazol-4-ylcarboxylic ester to5-difluoromethylpyrazol-4-ylcarboxylic ester of at least 10:1 andfrequently of at least 20:1.

Work-up of the reaction mixtures obtained and isolation of the compoundof the formula (III) is carried out in a customary manner, for instanceby removing the solvent, for example under reduced pressure, by aqueousextractive work-up or by a combination of these measures. Furtherpurification may be carried out, for example, by a crystallization or bychromatography. Frequently, the product is already obtained in a puritywhich makes further purification steps redundant.

When converting the compounds of the formula (I) intodifluoromethylpyrazolyl-carboxylic esters, the amines of the formulaNHR²R³ are obtained as a byproduct. These amines can be isolated bysuitable measures known to the person skilled in the art and be used forproviding compounds of the formula (II). The isolation of the amines ofthe formula NHR²R³ can be carried out, for example, by customaryseparation methods, such as precipitation by adjusting the pH, or byextraction.

The compounds of the formula (III) can be hydrolyzed to give thecorresponding difluoromethyl-substituted pyrazol-4-ylcarboxylic acids.

Accordingly, a further subject matter of the invention relates to aprocess for preparing a pyrazol-4-carboxylic acid of the formula (V)

in which R⁴ has one of the meanings given above, comprising theprovision of a compound of the formula (III) as defined above by aprocess according to the invention and the hydrolysis of the esterfunction in the compound of the formula (III), whereby thepyrazolecarboxylic acid of the formula (V) is obtained.

In a specific embodiment of the process according to the invention forpreparing compounds of the formula (V), a reaction mixture provided by aprocess according to the invention for preparing compounds of theformula (III) and comprising a compound of the formula (III) ishydrolyzed without prior isolation of the compound of the formula (III).

The hydrolysis of the ester function in the compound (III) can becarried out with acid catalysis or basically or in another way. Thecompound (III) can be employed as such, i.e. after isolation. However,it is also possible to react the reaction mixture obtained in step b),if appropriate after removal of volatile components, such as solvents,without isolation of the compound of the formula (III).

In the basic hydrolysis of the compound (III), the compound of theformula (III) is usually treated with an alkali metal hydroxide oralkaline earth metal hydroxide, such as sodium hydroxide, potassiumhydroxide or lithium hydroxide, preferably with an aqueous alkali metalhydroxide solution or alkaline earth metal hydroxide solution,specifically an aqueous NaOH solution or an aqueous KOH solution, untilthe ester is completely hydrolyzed, preferably with heating.

In the basic hydrolysis, the molar ratio of the compound of the formula(III) to the base is usually in the range of from 0.8:1 to 1:10 and isin particular about equimolar, for example in the range of from 0.8:1 to1.2:1; however, a relatively large excess of base, for example of up to5 mol per mole of the compound (III), may also be advantageous.

The basic hydrolysis is usually carried out in a diluent or solvent. Inaddition to water, suitable diluents or solvents are also mixtures oforganic solvents stable towards alkali, with water. Examples of organicsolvents which are stable to alkali are in particular the C₁-C₄-alcoholsmentioned above, and also the acyclic and cyclic ethers mentioned above.

Also suitable are mixtures of nonpolar solvents, for example aromatichydrocarbons, such as benzene, toluene, xylenes, or (cyclo)aliphatichydrocarbons, such as hexane, cyclohexane and the like, with water.

The basic hydrolysis is preferably carried out at temperatures of from20 to 100° C. In general, the upper temperature limit is the boilingpoint of the solvent used, provided the reaction is carried out atatmospheric pressure. Preferably, a reaction temperature of 100° C. andin particular of 90° C. is not exceeded. Here, the reaction time dependson the reaction temperature and on the concentration and the stabilityof the ester compound in question. In general, the reaction conditionsare chosen such that the reaction time is in the range of from 0.5 to 12h and in particular in the range of from 1 to 6 h.

The acidic hydrolysis of the ester group of the compound (III) can becarried out analogously to known acidic ester hydrolyses, i.e. in thepresence of catalytic or stoichiometric amounts of an acid and water(see, for example, J. March, Advanced Organic Chemistry, 2nd ed.,334-338, McGraw-Hill, 1977 and the literature cited therein).Frequently, the reaction is carried out in a mixture of water and anaprotic organic solvent, for example an ether, as mentioned above.Examples of suitable acids are hydrohalic acids, sulfuric acid, organicsulfonic acids, such as p-toluenesulfonic acid or methanesulfonic acid,phosphoric acid and also acidic ion exchange resins and the like.

Suitable hydrolysis catalysts are furthermore alkali metal iodides,lithium iodide, trimethyliodosilane or mixtures of trimethylchlorosilanewith alkali metal iodides, such as lithium iodide, sodium iodide orpotassium iodide.

The acid (V) is isolated by customary separation methods, such as, forexample, by precipitation via adjusting the pH, or by extraction.

It has been found to be particularly advantageous, when using mixturesof nonpolar solvents with water as reaction medium, to separate the acidof the formula (V) under basic pH conditions as a solution in theaqueous phase, followed by precipitation as a solid from the aqueoussolution by adjusting an acidic pH. If the compounds of the formula(III) are hydrolyzed in the form of a reaction mixture provided by aprocess according to the invention, without prior isolation of thecompound of the formula (III), this procedure affords, as a byproduct ofthe precursor, the amine of the formula NHR²R³ as a solution in theseparated organic phase, and the amine can be used for providingcompounds of the formula (II).

The compounds of the general formulae (III) and (V) are suitable forsynthesizing a large number of compounds which are of interest as activecompounds, such as, for example, for preparing3-difluoromethylpyrazol-4-carboxamides, in particular3-difluoromethylpyrazol-4-carboxanilides.

Suitable methods for preparing anilides by reacting carboxylic acids orcarbonyl halides with aromatic amines are known to the person skilled inthe art, for example from the prior art cited at the outset, and alsofrom J. March, Advanced Organic Chemistry, 2nd ed., 382 f, McGraw-Hill,1977 and Organikum, 21st edition, Wiley-VCH, Weinheim 2001, pp. 481-484and the literature cited therein.

Examples of 3-difluoromethylpyrazol-4-carboxamides which can be preparedby this route are:

-   N-(2-bicyclopropyl-2-ylphenyl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,-   N-(3′,4′,5′-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,-   N-(2′,4′,5′-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,-   N-(3′,4′-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′,4′-difluoro-3-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′-chloro-4′-fluoro-3-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′,4′-dichloro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′,4′-difluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′-chloro-4′-fluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′,4′-dichloro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′,4′-difluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N-(3′-chloro-4′-fluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-ylcarboxamide,-   N[2-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl]-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxamide,-   N[4′-(trifluoromethylthio)-biphenyl-2-yl]-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxamide,-   3-(difluoromethyl)-1-methyl-N-[1,2,3,4-tetrahydro-9-(1-methylethyl)-1,4-methanonaphthalen-5-yl]-1H-pyrazol-4-ylcarboxamide,-   N-(3′-chloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(4′-chloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(4′-chlorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(4′-bromobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(4′-iodobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(3′,5′-difluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,-   N-(2-bromo-4-fluorophenyl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide    and-   N-(2-iodo-4-fluorophenyl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide.

Hereinbelow, the present invention is illustrated in more detail bynon-limiting examples.

EXAMPLES 1. Preparation of Compounds of the Formula (I) PreparationExample I.1 ethyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate (Alternative 1)

Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) and triethylamine(5.2 g, 51 mmol) were initially charged in 100 ml of toluene and cooledto −30° C. At this temperature, difluoroacetyl fluoride (5 g, 51 mmol)was then introduced. The reaction mixture was stirred at −30° C. for 3 hand then, over a period of 1 h, warmed to room temperature. The reactionmixture was washed with deionized water (50 ml). After separation of thephases, the aqueous phase was extracted once with toluene (100 ml). Thetoluene phases were combined and washed with an aqueous saturated NaClsolution (100 ml), and the solvent was then removed under reducedpressure. This gave ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 13.0 g; purity according to GC: 91.2%; yield: 94%). ¹H-NMR(CDCl₃): δ=1.3 (t, 3H), 1.75 (m, 6H), 3.3 (m, 2H), 3.6 (m, 2H), 4.25 (q,2H), 6.6 (t, 1H), 7.85 ppm (s, 1H).

Preparation Example I.2 ethyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate (Alternative 2)

Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initiallycharged in toluene (100 ml) and cooled to −30° C. At this temperature,difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced into thereaction mixture. Triethylamine (5.2 g, 51 mmol) was then added to thereaction mixture. The reaction mixture was stirred at −30° C. for 3 hand then, over a period of 1 hour, warmed to room temperature. Thereaction mixture was washed with deionized water (50 ml). Afterseparation of the phases, the aqueous phase was extracted once withtoluene (100 ml). The toluene phases were combined and washed with anaqueous saturated NaCl solution (100 ml) and the solvent was thenremoved under reduced pressure. This gave ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 12.6 g; purity according to GC: 85.5%; yield: 85.5%).

Preparation Example I.3 ethyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate (Alternative 3)

Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initiallycharged in toluene (100 ml) and cooled to −30° C. At this temperature,difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced. Triethylamine(7.7 g, 77 mmol) was then added to the reaction mixture. The reactionmixture was stirred at −30° C. for 3 h and then, over a period of 1 h,warmed to room temperature. The reaction mixture was washed withdeionized water (50 ml). After separation of the phases, the aqueousphase was extracted once with toluene (100 ml). The toluene phases werecombined and washed with an aqueous saturated NaCl solution (100 ml),and the solvent was then removed under reduced pressure. This gave ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 12.3 g; purity according to GC: 85.4%; yield: 83.4%).

Preparation Example I.4 ethyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate (Alternative 4)

Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initiallycharged in toluene (100 ml) and cooled to −30° C. At this temperature,difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced. Tributylamine(9.5 g, 51 mmol) was then added to the reaction mixture. The reactionmixture was stirred at −30° C. for 3 h and then, over a period of 1hour, warmed to room temperature. The reaction mixture was washed withdeionized water (50 ml). After separation of the phases, the aqueousphase was extracted once with toluene (100 ml). The toluene phases werecombined and washed with an aqueous saturated NaCl solution (100 ml) andthe solvent was then removed under reduced pressure. This gave ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 12.7 g; purity according to GC: 82.15%; yield: 82.8%).

Preparation Example I.5 methyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate

Methyl 3-piperidin-1-ylacrylate (96.7%, 50.7 g, 289 mmol) andtriethylamine (31.07 g, 307 mol) were initially charged in toluene (300ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride(30.1 g 307 mmol) was introduced. The reaction mixture was stirred at−30° C. for 3 h and then, over a period of 1 hour, warmed to roomtemperature. The reaction mixture was washed with deionized water (150ml). After separation of the phases, the aqueous phase was extractedonce with toluene (100 ml). The toluene phases were combined and washedwith an aqueous saturated NaCl solution (100 ml), and the solvent wasthen removed under reduced pressure.

This gave methyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 69.7 g; purity according to GC: 92.3%; yield: 90%). ¹H-NMR(CDCl₃): δ=1.75 (m, 6H), 3.3 (m, 2H), 3.62 (m, 2H), 3.75 (s, 3H), 6.62(t, 1H), 7.89 ppm (s, 1H).

Preparation Example I.6 Methyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate (comparativeexample for 1.5, not according to the invention)

Methyl 3-piperidin-1-ylacrylate (99%, 26.6 g, 155 mmol) andtriethylamine (17.3 g, 171 mmol) were initially charged in toluene (300ml) and cooled to −30° C. At this temperature, difluoroacetyl chloride(20 g, 171 mmol) was introduced. The reaction mixture was stirred at−30° C. for 3 h, another 200 ml of toluene were added to keep thesuspension stirrable and the mixture was then warmed to room temperatureover a period of 1 hour. The reaction mixture was washed with deionizedwater (200 ml). After separation of the phases, the aqueous phase wasextracted once with toluene (100 ml). The toluene phases were combinedand washed with an aqueous saturated NaCl solution (100 ml), and thesolvent was then removed under reduced pressure. This gave methyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 37.6 g; purity according to quant. NMR: 82.2%; yield:80.3%).

Preparation Example I.7 methyl4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate

Methyl 3-piperidin-1-ylacrylate (99%, 8.7 g, 51 mmol) and pyridine (4.26g, 54 mmol) was initially charged in toluene (150 ml) and cooled to −30°C. At this temperature, difluoroacetyl fluoride (10 g, 61 mmol) wasintroduced. The reaction mixture was stirred at −30° C. for 3 h andthen, over a period of 1 hour, warmed to room temperature. The reactionmixture was washed with deionized water (200 ml). After separation ofthe phases, the aqueous phase was extracted once with toluene (100 ml).The toluene phases were combined and washed with an aqueous saturatedNaCl solution (100 ml), and the solvent was then removed under reducedpressure. This gave methyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orangeoil (amount: 12.0 g; purity according to GC: 97.7%; yield: 93.2%).

Preparation Example I.8 methyl4,4-difluoro-3-oxo-2-(morpholin-4-ylmethylidene)butyrate

Methyl 3-morpholin-4-ylacrylate (96.3%, 8.5 g, 50 mmol) andtriethylamine (5.2 g, 50 mmol) were initially charged in toluene (250ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride(5.0 g, 50 mmol) was introduced. The reaction mixture was stirred at−30° C. for 3 h and then, over a period of 1 hour, warmed to roomtemperature. Under reduced pressure, the reaction mixture was freed fromthe solvent. The residue obtained was 15.5 g of an orange solid which,according to quant. ¹H-NMR, consisted to 66.4% of methyl4,4-difluoro-3-oxo-2-(morpholin-4-ylmethylidene)butyrate (yield: 82%).¹H-NMR (CDCl₃): δ=3.4 (m, 2H), 3.7 (m, 2H), 3.75 (s, 3H), 3.85 (m, 2H),6.6 (t, 1H), 7.85 ppm (s, 1H).

Preparation Example I.9 methyl4,4-difluoro-3-oxo-2-(2,6-dimethylmorpholin-4-ylmethylidene)butyrate

Methyl 3-(2,6-dimethylmorpholin-4-yl)acrylate (93.5%, 17.5 g, 82 mmol)and triethylamine (8.8 g, 87 mmol) were initially charged in toluene(150 ml) and cooled to −30° C. At this temperature, difluoroacetylfluoride (10.0 g, 100 mmol) was introduced. The reaction mixture wasstirred at −30° C. for 3 h and then, over a period of 1 hour, warmed toroom temperature. The reaction mixture was washed with deionized water(100 ml). After separation of the phases, the aqueous phase wasextracted once with toluene (100 ml). The toluene phases were combinedand washed with an aqueous saturated NaCl solution (100 ml), and thesolvent was then removed under reduced pressure. The residue obtainedwas 21.4 g of an orange solid which, according to GC analysis, consistedto 90.8% of methyl4,4-difluoro-3-oxo-2-(2,6-dimethylmorpholin-4-ylmethylidene)butyrate(yield: 85.3%). ¹H-NMR (CDCl₃): δ=1.2 (s, 3H), 1.25 (s, 3H), 2.95 (m,1H), 3.25 (m, 1H), 3.5 (m, 1H), 3.75 (m, 2H), 3.8 (s, 3H), 6.6 (t, 1H),7.85 ppm (s, 1H).

2. Preparation of Compounds of the Formula (III) Preparation ExampleIII.1 ethyl 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate(Alternative 1)

Methylhydrazine (0.33 g, 7 mmol) was dissolved in toluene (50 ml) andcooled to −50° C. At this temperature, a solution of ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (85.5%, 2.0g, 6.5 mmol) in toluene (50 ml) was added dropwise to the reactionmixture. The reaction mixture was stirred at −50° C. for 2 h and then,over a period of 1 hour, warmed to room temperature. Under reducedpressure, the reaction mixture was then freed from the solvent. Theresidue was dissolved in ethyl acetate (50 ml) and washed with deionizedwater (50 ml). The organic phase was dried over MgSO₄, and the solventwas then removed under reduced pressure. The residue obtained was ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (amount: 1.7 g;purity according to GC: 76.3% (based on the 3-isomer); yield: 97%). Theisomer ratio of 3-isomer to 5-isomer in the residue was 97:3. ¹H-NMR(CDCl₃): δ=1.35 (t, 3H), 3.95 (s, 2H), 4.3 (q, 2H), 7.12 (t, 1H), 7.9ppm (s, 1H).

Preparation Example III.2 ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (Alternative 2)

An aqueous solution of methylhydrazine (35%, 0.95 g, 7 mmol) was mixedwith toluene (50 ml) and cooled to −50° C. At this temperature, asolution of ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (85.5%, 2.0g, 6.5 mmol) in toluene (50 ml) was added dropwise to the reactionmixture. The reaction mixture was stirred at −50° C. for 2 h and then,over a period of 1 hour, warmed to room temperature. Under reducedpressure, the reaction mixture was then freed from the solvent. Theresidue was dissolved in ethyl acetate (50 ml) and washed with deionizedwater (50 ml). The organic phase was dried over MgSO₄, and the solventwas then removed under reduced pressure. The residue obtained was ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (amount: 1.7 g;purity according to GC: 59.3% (based on the 3-isomer); yield: 75.4%).The isomer ratio of 3-isomer to 5-isomer in the residue was 76:24.

Preparation Example III.3 ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (Alternative 3)

An aqueous solution of methylhydrazine (35%, 0.95 g, 7 mmol) was mixedwith triethylamine (0.66 g, 6.5 mol) and toluene (50 ml) and cooled to−50° C. At this temperature, a solution of ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)-butyrate (85.5%, 2.0g, 6.5 mmol) in toluene (50 ml) was added dropwise. The reaction mixturewas stirred at −50° C. for 2 h and then, over a period of 1 hour, warmedto room temperature. Under reduced pressure, the reaction mixture wasthen freed from the solvent. The residue was dissolved in ethyl acetate(50 ml) and washed with deionized water (50 ml). The organic phase wasdried over MgSO₄, and the solvent was then removed under reducedpressure. The residue obtained was ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (amount: 1.8 g;purity according to GC: 64.5% (based on the 3-isomer); yield: 73.4%).The isomer ratio of 3-isomer to 5-isomer in the residue was 84:16.

Preparation Example III.4 ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (Alternative 4)

An aqueous solution of methylhydrazine (35%, 0.95 g, 7 mmol) was mixedwith molecular sieve (5.0 g) and toluene (50 ml) and cooled to −50° C.At this temperature, a solution of ethyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (85.5%, 2.0g, 6.5 mmol) in toluene (50 ml) was added dropwise. The reaction mixturewas stirred at −50° C. for 2 h and then, over a period of 1 hour, warmedto room temperature. The reaction mixture was then filtered and freedfrom the solvent under reduced pressure. The residue was dissolved inethyl acetate (50 ml) and washed with deionized water (50 ml). Theorganic phase was dried over MgSO₄, and the solvent was then removedunder reduced pressure. The residue obtained was ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (amount: 1.3 g;purity according to GC: 72.9% (based on the 3-isomer); yield: 71.0%).The isomer ratio of 3-isomer to 5-isomer in the residue was 88:12.

Preparation Example III.5 ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (Alternative 5)

An aqueous solution of methylhydrazine (35%, 1.03 g, 8 mmol) was mixedwith aqueous sodium hydroxide solution (10%, 2.6 g, 6.5 mmol) andethanol (50 ml) and cooled to −3° C. At this temperature, a solution ofethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (85.5%,2.0 g, 6.5 mmol) in toluene (50 ml) was added dropwise. The reactionmixture was stirred at −3° C. for 2 h and then, over a period of 1 hour,warmed to room temperature. Under reduced pressure, the reaction mixturewas then freed from the solvent. The residue was dissolved in ethylacetate (50 ml) and washed with deionized water (50 ml). The organicphase was dried over MgSO₄, and the solvent was then removed underreduced pressure. The residue obtained was ethyl3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (amount: 1.0 g;purity according to GC: 80.6% (based on the 3-isomer); yield: 66.3%).The isomer ratio of 3-isomer to 5-isomer in the residue was 98:2.

Preparation Example III.6 methyl3-difluoromethyl-1H-pyrazol-4-yl-carboxylate

At −50° C., a solution of methyl4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (97.9%, 20.0g, 79 mmol) in toluene (150 ml) was added dropwise to a solution ofhydrazine hydrate (100%, 4.36 g, 87 mmol) in toluene (150 ml). Thereaction mixture was stirred at −50° C. for 2 h and then, over a periodof 1 hour, warmed to room temperature. The reaction mixture was washedwith deionized water (100 ml). After separation of the phases, theaqueous phase was extracted once with toluene (100 ml). The toluenephases were combined and washed with an aqueous saturated NaCl solution(100 ml), and the solvent was then removed under reduced pressure.

According to GC analysis, the residue obtained (9.2 g) consisted to65.3% of methyl 3-difluoromethyl-1H-pyrazol-4-yl-carboxylate (Yield:66%). ¹H-NMR (CDCl₃): δ=3.9 (s, 3H), 7.25 (t, 1H), 8.2 ppm (s, 1H).

3. Preparation of Compounds of the Formula (V) Preparation Example V.13-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid

A mixture of ethyl 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate(1.4 g, 52 mmol) and aqueous sodium hydroxide solution (10% strength,3.1 g, 8 mmol) was stirred at 60° C. for 2 h. The reaction mixture wascooled to room temperature, and the pH was then adjusted to 1 usingconcentrated hydrochloric acid. The reaction mixture was cooled furtherto 0° C., resulting in the precipitation of a solid. The precipitatedsolid was filtered off, washed with cyclohexane and dried under reducedpressure. This gave 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylicacid as a solid (amount: 0.8 g; yield: 87%). ¹H-NMR (DMSO-d₆): δ=3.9 (s,2H), 7.2 (t, 1H), 8.35 ppm (s, 1H).

Preparation Example V.23-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid (one-pot batch)

At −30° C., difluoroacetyl fluoride (18.7 g, 0.187 mol; 98%) wasintroduced into a solution of methyl 3-piperidin-1-ylacrylate (99%,29.05 g, 0.17 mol) and triethylamine (25.8 g, 0.255 mol) in toluene (250ml). The reaction mixture was stirred at −30° C. for 3 h and then, overa period of 1 hour, warmed to room temperature. The reaction mixture waswashed with deionized water (250 ml). After separation of the phases,the aqueous phase was extracted once with toluene (200 ml). The toluenephases were combined and, under reduced pressure, concentrated to about350 ml. The reaction solution obtained in this manner was, at −50° C.,added dropwise to a solution of methylhydrazine (8.78 g, 0.187 mol) intoluene (150 ml). The reaction mixture was stirred at −50° C. for 2 hand then, over a period of 1 hour, warmed to room temperature. Aqueoussodium hydroxide solution (10%, 105.3 g, 0.263 mol) was then added, andthe reaction mixture was heated under reflux conditions for 2 h. Aftercooling to room temperature, the phases were separated. The toluenephase was extracted with aqueous sodium hydroxide solution (10%strength, 100 ml). The aqueous phases were combined, adjusted to a pH of1 using hydrochloric acid (conc.) and cooled to 0° C. The precipitatedsolid was filtered off, washed with cyclohexane and dried at 60° C.under reduced pressure. This gave3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid in an amount of21.1 g (65% yield) in a purity of 91% (according to quant. HPLC). ¹H-NMR(CDCl₃): δ=3.85 (s, 2H), 3.95 (s, 3H), 7.12 (t, 1H), 7.9 ppm (s, 1H).

1. A process for preparing compounds of the formula (I)

in which R¹ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₃-C₁₀-cycloalkyl or benzyl, where the two last mentioned radicals areunsubstituted or have 1, 2 or 3 substituents independently of oneanother selected from the group consisting of halogen, CN, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; R² andR³ independently of one another are C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₃-C₁₀-cycloalkyl or benzyl, where the two last mentionedradicals are unsubstituted or have 1, 2 or 3 substituents independentlyof one another selected from the group consisting of halogen, CN, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; or R²together with R³ and the nitrogen atom to which the two radicals areattached are an optionally substituted 5- to 10-membered heterocyclicradical which, in addition to the nitrogen atom, may contain a further1, 2 or 3 heteroatoms selected from the group consisting of O, N and Sas ring members; comprising reacting a compound of the formula (II)

with difluoroacetyl fluoride.
 2. The process according to claim 1 inwhich R² together with R³ and the nitrogen atom to which the tworadicals are attached are an optionally substituted 5- to 10-memberedheterocyclic ring which, in addition to the nitrogen atom, may contain afurther 1, 2 or 3 heteroatoms selected from the group consisting of O, Nand S as ring members.
 3. The process according to claim 2 in whichNR²R³ is a saturated, optionally substituted 5- or 6-memberedheterocyclic radical which, in addition to the nitrogen atom, maycontain a further heteroatom selected from the group consisting of O, Nand S as ring member.
 4. The process according to claim 3 in which NR²R³is pyrrolidin-1-yl, oxazolidin-3-yl, 3-methylimidazolin-1-yl,piperidin-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl.
 5. The processaccording to claim 1 where the reaction of the compound of the formula(II) with difluoroacetyl fluoride is carried out essentiallyanhydrously.
 6. The process according to claim 1 wherein the compound ofthe formula (II) is reacted with difluoroacetyl fluoride withoutaddition of a base.
 7. The process according to claim 1 wherein thecompound of the formula (II) is reacted with difluoroacetyl fluoride inthe presence of a base.
 8. The process according to claim 7 where thebase is selected from organic bases.
 9. The process according to claim 8where the base is selected from tertiary amines.